(Hypertension. 1998;31:349.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
AT2 Receptor Stimulation Increases Aortic Cyclic GMP in SHRSP by a Kinin-Dependent Mechanism
Institute of Pharmacology, Christian-Albrechts University of Kiel and German Institute for High Blood Pressure Research, Heidelberg, Germany.
Correspondence to Peter Gohlke, PhD, Institute of Pharmacology, Christian-Albrechts University of Kiel, Hospitalstrasse 4, 24105 Kiel, Germany
In the present study we tested the hypothesis whether an angiotensin AT2 receptor-mediated stimulation of the bradykinin (BK)/nitric oxide (NO) system can account for the effects of AT1 receptor antagonism on aortic cGMP described previously in SHRSP. Adult SHRSP were treated for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or vehicle (0.9% NaCl IV). Animals were pretreated with vehicle, losartan (100 mg/kg PO), PD 123319 (30 mg/kg IV), losartan plus PD 123319, icatibant (500 µg/kg IV), NG-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg IV), or minoxidil (3 mg/kg IV). Mean arterial blood pressure (MAP) was continuously monitored over the 4-hour experimental period, and plasma ANG II and aortic cGMP were measured by RIA at the end of the study. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II as well as minoxidil plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated animals, respectively. Plasma levels of ANG II were increased 2-fold by ANG II infusion alone or by ANG II in combination with icatibant, L-NAME, or minoxidil. The increase in plasma ANG II levels was even more pronounced after losartan treatment. Aortic cGMP content was significantly increased by ANG II, losartan, losartan plus ANG II, and minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05). The effects of ANG II and of losartan plus ANG II on aortic cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319. Icatibant and L-NAME abolished the effects of ANG II on aortic cGMP. Our results demonstrate the following: (1) ANG II increases aortic cGMP by an AT2 receptor-mediated action because the effect could be prevented by an AT2 receptor antagonist; (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with minoxidil; (3) losartan increased aortic cGMP most likely by increasing plasma ANG II levels with a subsequent stimulation of AT2 receptors; and (4) the effects of AT2 receptor stimulation are mediated by BK and, subsequently, NO because they were abolished by B2 receptor blockade as well as by NO synthase inhibition.
Key Words: angiotensin II • AT1 receptor antagonist • AT2 receptor • bradykinin • nitric oxide • cGMP • losartan
Abbreviations: ANG II = angiotensin II • BK = bradykinin • L-NAME = NG-nitro-L-arginine methyl ester • MAP = mean arterial blood pressure • NO = nitric oxide • RAS = renin-angiotensin system • SHRSP = stroke-prone spontaneously hypertensive rats
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M. Lauth, M. Cattaruzza, and M. Hecker ACE Inhibitor and AT1 Antagonist Blockade of Deformation-Induced Gene Expression in the Rabbit Jugular Vein Through B2 Receptor Activation Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 61 - 66. [Abstract] [Full Text] [PDF]
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G. Nickenig, A. Stablein, S. Wassmann, C. Wyen, C. Muller, and M. Bohm Acute effects of ACE inhibition on coronary endothelial dysfunction Journal of Renin-Angiotensin-Aldosterone System, December 1, 2000; 1(4): 361 - 364. [Abstract] [PDF]
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 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
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 J. A. Olivares-Reyes, S. Jayadev, L. Hunyady, K. J. Catt, and R. D. Smith Homologous and Heterologous Phosphorylation of the AT2 Angiotensin Receptor by Protein Kinase C Mol. Pharmacol., November 1, 2000; 58(5): 1156 - 1161. [Abstract] [Full Text]
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M. C. DE GRACIA, A. OSUNA, F. O'VALLE, R. G. DEL MORAL, R. WANGENSTEEN, C. G. DEL RIO, and F. VARGAS Deoxycorticosterone Suppresses the Effects of Losartan in Nitric Oxide--Deficient Hypertensive Rats J. Am. Soc. Nephrol., November 1, 2000; 11(11): 1995 - 2000. [Abstract] [Full Text]
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Y. Xu, A. S. Clanachan, and B. I. Jugdutt Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade Hypertension, October 1, 2000; 36(4): 506 - 510. [Abstract] [Full Text] [PDF]
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K. D. Croft, J. C. McGiff, A. Sanchez-Mendoza, and M. A. Carroll Angiotensin II releases 20-HETE from rat renal microvessels Am J Physiol Renal Physiol, September 1, 2000; 279(3): F544 - F551. [Abstract] [Full Text] [PDF]
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 H. Kraiczi, J. Hedner, Y. Peker, and J. Carlson Increased vasoconstrictor sensitivity in obstructive sleep apnea J Appl Physiol, August 1, 2000; 89(2): 493 - 498. [Abstract] [Full Text] [PDF]
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J. E. Bishop, L. A. Kiernan, H. E. Montgomery, P. Gohlke, and J. R. McEwan Raised blood pressure, not renin-angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats Cardiovasc Res, July 1, 2000; 47(1): 57 - 67. [Abstract] [Full Text] [PDF]
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M. d. Gasparo, P. Hess, B. Nuesslein-Hildesheim, P. Bruneval, and J.-P. Clozel Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 151 - 158. [Abstract] [PDF]
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A. Nunez, J. Gomez, L. R. Zalba, M. Monton, A. Jimenez, S. Velasco, A. Lopez-Blaya, A. Celdran Uriarte, S. Casado, and A. Lopez-Farre Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 175 - 179. [Abstract] [PDF]
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Yi Xu, V. Menon, and B. I Jugdutt Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-{varepsilon} in acutely reperfused myocardial infarction in the dog: Effect of UP269-6 and losartan on AT1- and AT2-receptor expression and IP3 receptor and PKC{varepsilon} proteins Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 184 - 195. [Abstract] [PDF]
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W. Linz, H. Heitsch, B. A. Scholkens, and G. Wiemer Long-Term Angiotensin II Type 1 Receptor Blockade With Fonsartan Doubles Lifespan of Hypertensive Rats Hypertension, April 1, 2000; 35(4): 908 - 913. [Abstract] [Full Text] [PDF]
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M. Schachter ACE inhibitors, angiotensin receptor antagonists and bradykinin Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 27 - 29. [PDF]
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 S. Gallinat, S. Busche, M. K. Raizada, and C. Sumners The angiotensin II type 2 receptor: an enigma with multiple variations Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E357 - E374. [Abstract] [Full Text] [PDF]
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 D.J. van Veldhuisen and A.A. Voors Blockade of the renin angiotensin system in heart failure: the potential place of angiotensin II receptor blockers Eur. Heart J., January 1, 2000; 21(1): 14 - 16. [PDF]
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B. I. Jugdutt, Yi Xu, M. Balghith, R. Moudgil, and V. Menon Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R, IP3R and PKC{varepsilon} Proteins and cGMP Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 301 - 311. [Abstract] [PDF]
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R. M. Carey, Z.-Q. Wang, and H. M. Siragy Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function Hypertension, January 1, 2000; 35(1): 155 - 163. [Abstract] [Full Text] [PDF]
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H. MATSUDA, K. HAYASHI, K. ARAKAWA, M. NAITOH, E. KUBOTA, M. HONDA, A. MATSUMOTO, H. SUZUKI, T. YAMAMOTO, F. KAJIYA, et al. Zonal Heterogeneity in Action of Angiotensin-Converting Enzyme Inhibitor on Renal Microcirculation: Role of Intrarenal Bradykinin J. Am. Soc. Nephrol., November 1, 1999; 10(11): 2272 - 2282. [Abstract] [Full Text]
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M. N. Barber, D. B. Sampey, and R. E. Widdop AT2 Receptor Stimulation Enhances Antihypertensive Effect of AT1 Receptor Antagonist in Hypertensive Rats Hypertension, November 1, 1999; 34(5): 1112 - 1116. [Abstract] [Full Text] [PDF]
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K. Matrougui, L. Loufrani, C. Heymes, B. I. Levy, and D. Henrion Activation of AT2 Receptors by Endogenous Angiotensin II Is Involved in Flow-Induced Dilation in Rat Resistance Arteries Hypertension, October 1, 1999; 34(4): 659 - 665. [Abstract] [Full Text] [PDF]
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K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
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W. Linz, P. Wohlfart, B. A Scholkens, T. Malinski, and G. Wiemer Interactions among ACE, kinins and NO Cardiovasc Res, August 15, 1999; 43(3): 549 - 561. [Full Text] [PDF]
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 H. M. Siragy, T. Inagami, T. Ichiki, and R. M. Carey Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor PNAS, May 25, 1999; 96(11): 6506 - 6510. [Abstract] [Full Text] [PDF]
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H. M. Siragy and R. M. Carey Protective Role of the Angiotensin AT2 Receptor in a Renal Wrap Hypertension Model Hypertension, May 1, 1999; 33(5): 1237 - 1242. [Abstract] [Full Text] [PDF]
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M. Horiuchi, M. Akishita, and V. J. Dzau Recent Progress in Angiotensin II Type 2 Receptor Research in the Cardiovascular System Hypertension, February 1, 1999; 33(2): 613 - 621. [Abstract] [Full Text] [PDF]
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N. H. Anderson, A. M. Devlin, D. Graham, J. J. Morton, C. A. Hamilton, J. L. Reid, N. J. Schork, and A. F. Dominiczak Telemetry for Cardiovascular Monitoring in a Pharmacological Study : New Approaches to Data Analysis Hypertension, January 1, 1999; 33(1): 248 - 255. [Abstract] [Full Text] [PDF]
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H. Matsubara Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases Circ. Res., December 14, 1998; 83(12): 1182 - 1191. [Abstract] [Full Text] [PDF]
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